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Immunosuppressants
Kinds of Immunosuppressants Terms modified by Immunosuppressants Selected AbstractsA NOVEL IMMUNOSUPPRESSANT, LF15-0195c, PREVENTS THE DEVELOPMENT OF ANTI-GBM DISEASE IN RATSNEPHROLOGY, Issue 3 2000Tesch Gh [source] Cyclosporin versus Tacrolimus as Primary Immunosuppressant After Liver Transplantation: A Meta-AnalysisAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2006V. C. McAlister A systematic review of randomized clinical trials (RCT) was undertaken to evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients. MEDLINE, EMBASE, Cochrane Central and Hepato-Biliary Group Controlled Trials Registers were searched. Using fixed and random effects model, relative risk (RR), values <1 favoring tacrolimus, with 95% confidence intervals (CI) were calculated. Of 717 potentially relevant references, 16 RCTs were eligible for inclusion. Mortality and graft loss at 1 year were significantly reduced in tacrolimus-treated recipients (Death: RR 0.85, 95% CI 0.73,0.99; graft loss: RR 0.73, 95% CI 0.61,0.86). Tacrolimus reduced the number of recipients with acute rejection (RR 0.81, 95% CI 0.75,0.88) and steroid-resistant rejection (RR 0.54, 95% CI 0.47,0.74) in the first year. Lymphoproliferative disorder or dialysis rates were not different but more de novo diabetes (RR 1.38, 95% CI 1.01,1.86) occurred with tacrolimus. More patients stopped cyclosporin than tacrolimus (RR 0.57, 95% CI 0.49,0.66). Treating 100 recipients with tacrolimus instead of cyclosporin would avoid rejection and steroid-resistant rejection in nine and seven patients respectively, graft loss and death in five and two patients respectively, but four additional patients would develop diabetes after liver transplantation. [source] Total Synthesis of Cyclic Tetrapeptide FR235222, a Potent Immunosuppressant that Inhibits Mammalian Histone Deacetylases.CHEMINFORM, Issue 46 2005Weiqing Xie No abstract is available for this article. [source] FR235222, a Fungal Metabolite, Is a Novel Immunosuppressant that Inhibits Mammalian Histone Deacetylase.CHEMINFORM, Issue 32 2003Part 3. No abstract is available for this article. [source] Interactions between Antiinfective Agents and ImmunosuppressantsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2009L. D. Thomas First page of article [source] Differential Dose Adjustments of Immunosuppressants after Resuming Boosted versus Unboosted HIV-Protease Inhibitors Postliver TransplantAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009G. Guaraldi Pharmacokinetic (PK) interactions between protease inhibitors (PIs) and immunosuppressive agents (IS) are critical elements in the management of HIV-infected patients who undergo liver transplantation (LTx). The primary objective of this study was to evaluate the decreases in IS dosages necessary to maintain an appropriate therapeutic window (TW) after initiating PI-based antiretroviral therapy regimens post-LTx. Single-center, PK cross-sectional study of consecutive HIV-infected adult patients who underwent LTx was done. Blood trough concentrations (Ct) of IS were obtained using a commercial MEIA test; plasma Ct of PIs were measured using HPLC. Twelve consecutive HIV-infected adult patients (11 males, 1 female) were enrolled. More rapid increases in IS plasma Ct were observed 48 h after initiating ritonavir (RTV)-boosted PI therapy post-LTx than when using unboosted PIs. Seven patients developed acute renal failure. The median fold decrease in IS dosages required to regain IS concentrations that were in the TW was 7.5 (range 6,14) after resuming boosted PIs and 2.9 (range 2,4) after unboosted PIs. The overall median time necessary to reach IS TW after dose adjustment was 3.5 days (range 0,15). Unboosted PIs exhibited lesser PK interactions with IS than did RTV-boosted PIs and were thus more amenable to use in the post-LTx setting. [source] Pharmacogenetics of Immunosuppressants: Progress, Pitfalls and PromisesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2008D. Cattaneo Most of the immunosuppressants used in organ transplantation are characterized by a narrow therapeutic index, whereby underdosing is associated with increased risk of rejection episodes and overdosing may exacerbate drug-related toxicity. Pharmacogenetics,complementary to pharmacokinetics,holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic actions while minimizing adverse effects. Most of the studies have focused on polymorphisms of genes involved in drug metabolism and distribution, but as of now, only thiopurine-S-methyltransferase and cytochrome P 450 3A5 genotypes appear to have sufficiently large influence to have potentialities in guiding drug dosing. This may reflect the fact that available information from other polymorphisms derives almost exclusively from retrospective observations or from studies with important methodological biases. Active investigations aimed at identifying allelic variants of gene encoding for the pharmacologic targets are now ongoing. Recent studies have demonstrated that also donor genotype may play a significant role in immunosuppressive drug pharmacokinetics and pharmacodynamics. As one of the main future tasks, it is mandatory to develop mathematical models able to incorporate multiple gene polymorphisms with pharmacokinetic data and other critical information, providing algorithms able to individualize the best immunosuppressive therapy for each patient before transplantation. [source] Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channelDIABETES OBESITY & METABOLISM, Issue 6 2001D. K. Fuhrer Summary Aim By focusing on the pancreatic , cell response to tacrolimus, cyclosporin A (CsA) and rapamycin we hoped to identify immunophilin, calcineurin and/or novel mechanism involvement and advance the understanding of immunosuppressant regulated insulin control. Methods A glucose responsive , cell model was established in which the glucose response was blocked by immunosuppressant treatment and this model was used to further characterise this effect. Quantification of insulin release to immunosuppressants and specific inhibitors was used to identify the mechanism involved. Results It was found that upon the addition of tacrolimus, rapamycin, or CsA, rapid and significant exocytosis of cellular insulin was seen. A dose response study of this effect revealed optimal concentration windows of 50, 80 nm for tacrolimus, 100,300 nm for rapamycin, and 7,12 mm for CsA in RIN-5F cells. Optimal insulin release for HIT-T15 cells was similar. Additional experiments demonstrate that immunosuppressant pretreatment blocked the subsequent immunosuppressant induced insulin release but not that of a thapsigargin control, suggesting that suppression and release are non-toxic, specific and in the same pathway. Further experiments showed that this insulin release was a calcium dependent process, which was blocked by inhibitors of l -type calcium channels. Continued studies showed that the specific ATP-sensitive potassium channel agonist diazoxide (150 mm) also blocked immunosuppressant-induced insulin release. Conclusions A model that fits this data is a novel calcineurin-independent immunophilin mediated partial closing of the ATP-sensitive potassium channel, which would lead to an initial insulin release but would reduce subsequent responses through this pathway. [source] Effect of in vitro and in vivo organotin exposures on the immune functions of murray cod (Maccullochella peelii peelii)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2007Andrew J. Harford Abstract Murray cod (Maccullochella peelii peelii) is an iconic native Australian freshwater fish and an ideal species for ecotoxicological testing of environmental pollutants. The species is indigenous to the Murray-Darling basin, which is the largest river system in Australia but also the ultimate sink for many environmental pollutants. The organotins tributyltin (TBT) and dibutyltin (DBT) are common pollutants of both freshwater and marine environments and are also known for their immunotoxicity in both mammals and aquatic organisms. In this study, TBT and DBT were used as exemplar immunotoxins to assess the efficiency of immune function assays (i.e., mitogen-stimulated lymphoproliferation, phagocytosis in head kidney tissue, and serum lysozyme activity) and to compare the sensitivity of Murray cod to other fish species. The organotins were lethal to Murray cod at concentrations previously reported as sublethal in rainbow trout (i.e., intraperitoneal [i.p.] lethal dose to 75% of the Murray cod [LD75] = 2.5 mg/kg DBT and i.p. lethal dose to 100% of the Murray cod [LD100] = 12.5 mg/kg TBT and DBT). In vivo TBT exposure at 0.1 and 0.5 mg/kg stimulated the phagocytic function of Murray cod (F = 6.89, df = 18, p = 0.004), while the highest concentration of 2.5 mg/kg TBT decreased lymphocyte numbers (F = 7.92, df = 18, p = 0.02) and mitogenesis (F = 3.66, df = 18, p = 0.035). Dibutyltin was the more potent immunosuppressant in Murray cod, causing significant reductions in phagocytic activity (F = 5.34, df = 16, p = 0.013) and lymphocyte numbers (F = 10.63, df = 16, p = 0.001). [source] Sphingosine-1-phosphate and FTY720 as anti-atherosclerotic lipid compoundsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2007M. Tölle Abstract All stages of atherosclerosis have been identified as a chronic vascular inflammatory disease. In the last few years there is increasing evidence that endogenous lysophospholipids such as sphingosine-1-phosphate (S1P) have potent anti-inflammatory properties. The S1P analogue FTY720 that has been developed as a potent, orally active, immunosuppressant in the field of transplantation and autoimmune disease has interesting effects on inflammatory processes in the arterial vessel wall. S1P targets five specific S1P receptors (S1P1,5), which are ubiquitously expressed. S1P1,3 receptor expression is identified in arterial vessels. S1P and FTY720 show potent silencing effects on some vascular proinflammatory mechanisms in endothelial and vascular smooth muscle cells. In addition, the interaction of monocytes with the vessel wall is inhibited. As shown recently, FTY720 can effectively reduce the progression of atherosclerosis in apolipoprotein E-deficient mice having a high-cholesterol diet. It is not entirely clear which S1P receptor subtype is mainly involved in this process. However, it is currently speculated that the S1P3 and probably the S1P1 is involved in the anti-atherosclerotic effects of FTY720. This review summarizes the current knowledge about S1P- and FTY720-effects on mechanisms of vascular inflammatory disease. In addition S1P receptor subtypes are identified which might be interesting for molecular drug targeting. [source] Is Age Associated with the Number or Types of Medications Prescribed to Renal Transplant Recipients?JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 3 2007Marie A. Chisholm PharmD OBJECTIVES: To determine whether age influences the number or types of medications prescribed to younger (aged 18,64) and elderly (aged ,65) renal transplant recipients 3 years posttransplant. DESIGN: A cross-sectional study involving renal transplant recipients. SETTING: Medical College of Georgia. PARTICIPANTS: A random sample of 100 elderly and 100 younger renal transplant recipients who received posttransplant care at the Medical College of Georgia, were on stable immunosuppressant therapy regimens, and were at least 3 years posttransplant. MEASUREMENTS: Medical and pharmacy data of recipients were evaluated for demographics; presence of a lipid-lowering agent; number of antihypertensives, immunosuppressants, antidiabetic agents, and total medications; number of rejections; dose per kilogram of immunosuppressant(s); infection-related hospitalizations; and measures of blood pressure, blood glucose, serum creatinine, serum tacrolimus/cyclosporine concentrations, total cholesterol, and triglycerides. RESULTS: Elderly recipients were more likely to have diabetes mellitus before the transplant and to develop diabetes mellitus afterwards (P=.04) and were prescribed more total medications (12.40±3.72 vs 10.25±4.07, P<.001) and antidiabetic agents (0.89±0.93 vs 0.42±0.77, P<.001) 3 years posttransplant than younger recipients. Elderly recipients also had fewer chronic rejections, more infection-related hospitalizations, lower diastolic blood pressure, and greater fasting blood glucose levels 3 years posttransplant (P<.05) than younger recipients. CONCLUSION: Future investigation should focus on deciphering the implications of the greater numbers of medications prescribed to elderly renal transplant recipients in terms of maximizing desired health outcomes (e.g., graft survival) and minimizing adverse drug-related experiences (e.g., infection). [source] Hepatotoxic effect of cyclosporin A in the mitochondrial respiratory chainJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2007Lilia Cristina De la Cruz Rodríguez Abstract Cyclosporin A (CyA), a potent immunosuppressant, was used to determine the hepatotoxic effect in long-term treatments. Male Wistar rats were used in these experiments. They were given CyA chronically at doses used in patients for 120 days, and at doses of 5, 10, 15 and 20 mg kg,1 day,1. These doses amount to CyA values in blood of 200 ± 24, 314 ± 40, 445 ± 33 and 598 ± 53 ng ml,1, respectively. A significant increase in glutamate dehydrogenase (GLDH) was found in the groups treated with 15 and 20 mg kg,1 day,1, which would point to mitochondria as the potential target of the toxic action of CyA. The mitochondrial respiratory chain of rat livers was studied in enzyme complexes I and II. Enzyme complex I was determined by spectrophotometry at 340 nm using NADH oxidase with the respirable substrate 10 mm NADH; enzyme complex II was determined by monitoring succinate dehydrogenase by oxymetry using the respirable substrate 10 mm succinate. The results show the inhibition of NADH oxidase in the groups treated with 10, 15 and 20 mg kg,1 day,1, an effect dependent both on time and on CyA concentration. Enzyme complex II showed a decrease in oxygen consumption. These findings were confirmed by histological studies (hematoxylin-eosin technique). Conclusions: Long-term treatment with CyA at doses of 15 and 20 mg kg,1 day,1, amounting to concentrations in blood of 445 ± 33 and 598 ± 53 ng ml,1, causes alterations in the mitochondria, revealed by the increase in serum GLDH and by the functional alteration of enzyme complexes I and II of the mitochondrial respiratory chain. Copyright © 2007 John Wiley & Sons, Ltd. [source] Molecular analysis of the thiopurine S-methyltransferase alleles in Bolivians and TibetansJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2005H.-F. Lu MT Summary Background:, Thiopurine drugs are used as immunosuppressant or cytotoxic drugs. Thiopurine S-methyltransferase (TPMT) methylates and thereby modulates the therapeutic and toxic effects of these drugs. The activity of TPMT is affected by genetic polymorphism of TPMT alleles, and these alleles have not been studied in Tibetans and Bolivians. Objectives:, To analyse the TPMT allelic frequencies in Tibetans and Bolivians. Methods:, We developed an inexpensive method for collecting blood and extracting genomic DNA. Genomic DNA was extracted from blood spots of 50 Tibetans and 115 Bolivians. The frequencies of allelic variants of TPMT gene (TPMT*1 to TPMT*8) were determined using polymerase chain reaction-restriction fragment length polymorphism technique. Results:, The allelic frequencies of TPMT*1 were 99 and 93·48% for Tibetans and Bolivians, respectively. The corresponding allelic frequencies of TPMT*3A were 0 and 6·52% and those of TPMT*3C were 1·0 and 0%. No TPMT*2, 3B, 3D, 4,8 were found in these two populations. Conclusions:, As with Caucasian populations, TPMT*3A is the most prevalent mutant allele in Bolivians. Our results may be of value in helping to guide the prescription of thiopurine drugs in these populations. [source] Systematic review: steroid withdrawal in anti-TNF-treated patients with inflammatory bowel diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010E. Bultman Aliment Pharmacol Ther 2010; 32: 313,323 Summary Background, The increasing awareness of increased risk for opportunistic infections when combining several immunosuppressant drugs led to new treatment goals for inflammatory bowel disease including limited use of steroids. Aim, To conduct a systematic review to establish figures for steroid withdrawal in anti-TNF treated inflammatory bowel disease-patients. Methods, Medline was searched using the search-terms Ulcerative Colitis (UC) [Mesh], Crohn Disease (CD) [Mesh], IBD [Mesh], crohn, colitis, IBD and steroid sparing, all combined with infliximab and adalimumab. We selected English-language publications that addressed the effect of anti-TNF on steroid withdrawal. Studies had to assess patients with luminal CD or UC. Numbers of patients who were able to withdraw steroids were calculated. Results, Six studies could be included; five reporting on infliximab and one on adalimumab. Studies were heterogeneously designed. Overall, in the adult population, up to 38% of the patients were able to withdraw corticosteroids during infliximab therapy. In the paediatric population, up to 75% of the patients were able to withdraw corticosteroids during infliximab therapy. Conclusions, Although a consensus on the definition of steroid-sparing is lacking, approximately two-thirds of the inflammatory bowel disease-patients are unable to withdraw corticosteroid treatment during anti-TNF therapy. [source] Late-onset Behçet's disease does not correlate with indolent clinical course: report of seven Taiwanese patientsJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 5 2008J Tsai Abstract Background, Behçet's disease (BD) is a recurrent multisystem disease of uncertain aetiology. The young adults are most often affected, usually during the third decade. Late occurrence of the disease is considered uncommon and less frequently investigated. Objective, The aim of this study was to examine the clinical features of BD patients with disease onset at a later age and compare them with the usual age of onset group. Methods, Retrospective review of clinical charts of BD patients was conducted. Patients with age of onset at or after 40 years of age were identified. The clinical profiles and medications required to control the disease activity were documented. Comparisons of clinical features and the medications used were made between patients with disease onset before and after 40 years of age. Results, Seven late-onset BD patients were identified. Among them, five patients required the use of systemic immunosuppressant in addition to colchicine and corticosteroid for adequate disease control. There is no significant difference in clinical profiles between patients with disease onset before and after 40 years of age, but the incidence of uveitis, an indicator of unfavourable prognosis, was surprisingly high. More specifically, it was noted in four of seven patients identified. Conclusion, Our findings indicate that the clinical course of BD is not indolent in the patients with late-onset BD. More importantly, physicians should be aware that BD can occur in older patients, and close attention regarding their disease activities is warranted as their clinical courses may not be as benign as previously believed. [source] European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society , First RevisionJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2010Joint Task Force of the EFNS, the PNS Background: Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been published (J Peripher Nerv Syst 2005; 10: 220,228, Eur J Neurol 2006; 13: 326,332). Objectives: To revise these guidelines. Methods: Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion. Recommendations: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point). [source] Long-term outcome of non-fistulizing (ulcers, stricture) perianal Crohn's disease in patients treated with infliximabALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2009G. BOUGUEN Summary Background, In Crohn's disease, anal ulcers and stricture can be disabling. Aim, To evaluate long-term outcome of non-fistulizing perianal Crohn's disease under infliximab. Methods, The medical records of 99 patients with non-fistulizing perianal Crohn's disease at first infliximab infusion were reviewed. Complete responses (ulcer healing or stricture regression) after induction infliximab therapy and at the maximal follow-up were assessed. Results, Ninety-four patients (94.9%) had ulcers, 22 (22.2%) had stricture and 31 (31.3%) had draining perianal fistulas at first infliximab infusion. After infliximab induction therapy, 40/94 (42.5%) patients with ulcers, 4/22 (18.2%) with stricture and 10/31 (32.2%) with fistulas had a complete response. Eight patients were lost to follow-up. After a median follow-up of 175 weeks (range, 13,459), complete response rates for ulcers, stricture and fistulas were 72.3% (68/94), 54.5% (12/22) and 54.8% (20/31) respectively. Long-term response for cavitating ulcer was positively associated with concomitant immunosuppressant use (P = 0.017) and older age (P = 0.049). Among the 12 patients with complete regression of stricture, 6 patients also had anal dilatation. Complete response was associated with perianal pain relief and disappearance of soiling. Three patients with ulcers developed an anal abscess. Conclusions, Infliximab therapy may be effective in inducing and maintaining response for ulcers. [source] Systematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes?ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009J. M. ANDREWS Summary Background, With greater use of immunomodulators in inflammatory bowel disease (IBD), it is uncertain whether concurrent therapy with both 5-aminosalicylic acid [5-ASA, mesalazine (mesalamine)] and an immunomodulator is necessary. Aim, To determine whether concurrent therapy with both 5-ASA and immunomodulator(s) improves outcomes in IBD. Methods, Systematic review with search terms ,azathioprine, 6-mercaptopurine, thiopurine(s), 5 aminosalicylic acid, mesalazine, inflammatory bowel disease, ulcerative colitis, Crohn's disease, immunosuppressant(s), immunomodulator and methotrexate' in November 2007 to identify clinical trials on concurrent 5-ASA and immunomodulator therapy. Results, Two small controlled studies were found. Neither showed a benefit on disease control beyond immunomodulator monotherapy. Potential pharmacological interactions exist between 5-ASA and thiopurines. Whilst circumstantial, epidemiological and laboratory evidence suggests that 5-ASA may assist colorectal cancer (CRC) chemoprevention, it may simply be via anti-inflammatory effects. With changes in practice, ethical issues and the long lead-time needed to demonstrate or disprove an effect, no clinical studies can/will directly answer this. The costs of avoiding one CRC in IBD may be as low as 153 times the annual cost of 5-ASA therapy. Conclusions, It is unclear whether concurrent 5-ASA and immunomodulator therapy improves outcomes of disease control, drug toxicity or compliance. Concurrent therapy of 5-ASA and immunomodulators may decrease CRC risk at ,acceptable' cost. [source] Meta-analysis of risk for relapse to substance use after transplantation of the liver or other solid organs,LIVER TRANSPLANTATION, Issue 2 2008Mary Amanda Dew For patients receiving liver or other organ transplants for diseases associated with substance use, risk for relapse posttransplantation is a prominent clinical concern. However, there is little consensus regarding either the prevalence or risk factors for relapse to alcohol or illicit drug use in these patients. Moreover, the evidence is inconsistent as to whether patients with pretransplantation substance use histories show poorer posttransplantation medical adherence. We conducted a meta-analysis of studies published between 1983 and 2005 to estimate relapse rates, rates of nonadherence to the medical regimen, and the association of potential risk factors with these rates. The analysis included 54 studies (50 liver, 3 kidney, and 1 heart). Average alcohol relapse rates (examined only in liver studies) were 5.6 cases per 100 patients per year (PPY) for relapse to any alcohol use and 2.5 cases per 100 PPY for relapse with heavy alcohol use. Illicit drug relapse averaged 3.7 cases per 100 PPY, with a significantly lower rate in liver vs. other recipients (1.9 vs. 6.1 cases). Average rates in other areas (tobacco use, immunosuppressant and clinic appointment nonadherence) were 2 to 10 cases per 100 PPY. Risk factors could be examined only for relapse to any alcohol use. Demographics and most pretransplantation characteristics showed little correlation with relapse. Poorer social support, family alcohol history, and pretransplantation abstinence of ,6 months showed small but significant associations with relapse (r = 0.17-0.21). Future research should focus on improving the prediction of risk for substance use relapse, and on testing interventions to promote continued abstinence posttransplantation. Liver Transpl 14:159,172. 2008. © 2008 AASLD. [source] Predicting immunosuppressant dosing in the early postoperative period with noninvasive indocyanine green elimination following orthotopic liver transplantationLIVER TRANSPLANTATION, Issue 1 2008Brian M. Parker Twenty adult patients undergoing orthotopic liver transplantation (OLT) were enrolled in this study, with the noninvasive indocyanine green plasma disappearance rate (ICG-PDR) measured both during and after OLT to assess the relationship between ICG-PDR and the ability of patients to achieve therapeutic postoperative tacrolimus immunosuppressant blood levels. Liver function was determined at both 2 and 18 hours post reperfusion with the ICG-PDR k value (1/min). Postoperative standard serum measures of liver function as well as liver biopsies were also collected and analyzed. The median ICG-PDR k value for the study group at 2 hours post reperfusion was 0.20 (0.16, 0.27), whereas at 18 hours post reperfusion, it was 0.22 (0.18, 0.35). The median change in the k value between the two ICG-PDR measurements was 0.05 (,0.02, 0.07) with P = 0.02. There was an interaction between the postoperative day 1 (18 hours post reperfusion) ICG-PDR k value and the linear increase in the tacrolimus blood level, such that the greater the k value was, the more gradual the observed rise was in tacrolimus over time [that is, the longer it took to achieve a therapeutic blood level (>12 ng/mL), P = 0.003]. Of the 16 patients that received tacrolimus, comparable dosing on a per kilogram body weight basis was observed. Also, no significant association between ICG-PDR k values and postoperative liver biopsy results was seen. This study demonstrates that the ICG-PDR measurement is a modality with the potential to assist in achieving adequate blood levels of tacrolimus following OLT. Liver Transpl 14:46,52, 2008. © 2007 AASLD. [source] Safety and risk of using pediatric donor livers in adult liver transplantationLIVER TRANSPLANTATION, Issue 1 2001Sukru Emre MD Pediatric donor (PD) livers have been allocated to adult transplant recipients in certain situations despite size discrepancies. We compared data on adults (age , 19 years) who underwent primary liver transplantation using livers from either PDs (age < 13 years; n = 70) or adult donors (ADs; age , 19 years; n = 1,051). We also investigated the risk factors and effect of prolonged cholestasis on survival in the PD group. In an attempt to determine the minimal graft volume requirement, we divided the PD group into 2 subgroups based on the ratio of donor liver weight (DLW) to estimated recipient liver weight (ERLW) at 2 different cutoff values: less than 0.4 (n = 5) versus 0.4 or greater (n = 56) and less than 0.5 (n = 21) versus 0.5 or greater (n = 40). The incidence of hepatic artery thrombosis (HAT) was significantly greater in the PD group (12.9%) compared with the AD group (3.8%; P = .0003). Multivariate analysis showed that preoperative prothrombin time of 16 seconds or greater (relative risk, 3.206; P = .0115) and absence of FK506 use as a primary immunosuppressant (relative risk, 4.477; P = .0078) were independent risk factors affecting 1-year graft survival in the PD group. In the PD group, transplant recipients who developed cholestasis (total bilirubin level , 5 mg/dL on postoperative day 7) had longer warm (WITs) and cold ischemic times (CITs). Transplant recipients with a DLW/ERLW less than 0.4 had a trend toward a greater incidence of HAT (40%; P < .06), septicemia (60%), and decreased 1- and 5-year graft survival rates (40% and 20%; P = .08 and .07 v DLW/ERLW of 0.4 or greater, respectively). In conclusion, the use of PD livers for adult recipients was associated with a greater risk for developing HAT. The outcome of small-for-size grafts is more likely to be adversely affected by longer WITs and CITs. The safe limit of graft volume appeared to be a DLW/ERLW of 0.4 or greater. [source] Effect of Baohuoside-1 aglycone and tacrolimus monotherapy and combination therapy on prevention of acute heart allograft rejection in the ratMICROSURGERY, Issue 4 2007Shijie Qi M.D. Baohuoside-1 (B-1), a recently introduced novel immunosuppressant that was proved to be potent in inhibition of T and B cell proliferation and B-1, also prevents cardiac allograft rejection in rodents. The present study further proved that monotherapy of B-1's analogue B-1 aglycone effectively prolongs cardiac allograft survival and combination therapy of B-1 aglycone with tacrolimus (FK506) produces synergistic effect in prevention acute cardiac allograft rejection in the rat. © 2007 Wiley-Liss, Inc. Microsurgery 2007. [source] Peripheral blood lymphocytes P-glycoprotein (P-gp, gp-170) expression in allogeneic kidney transplant patientsNEPHROLOGY, Issue 3 2006KATARZYNA KOTRYCH SUMMARY: Aim and Methods: P-glycoprotein (gp-170, P-gp) is a transmembrane transporter involved in drug, for example cyclosporine A, efflux from the cells thus limiting their intracellular concentration. Expression of the transporter on the surface of immune competent cells may be associated with poor prognosis in kidney transplant patients. The aim of the present study was to evaluate P-gp expression on the surface of CD4+, CD8+, CD19+ and CD56+ cells in kidney transplant patients treated with cyclosporine A as a main immunosuppressant, using flow cytometry. Results: It was found that P-gp expression in kidney transplant patients with acute rejection did not differ significantly from transplanted patients without rejection studied in the same period after transplantation, as well as from the healthy controls. Administration of 3-day course of 1000 mg/24 h methylprednisolone did not affect the expression of P-gp in the studied cells, except for significant elevation in CD56+ cells, which disappeared at 2 weeks after cessation of steroid administration. Conclusion: Based on the results from the present study it can be concluded that P-gp expression is not a prognostic factor of acute kidney graft rejection. [source] Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipientsPEDIATRIC TRANSPLANTATION, Issue 1 2010Carlos E. Araya Araya CE, Garin EH, Neiberger RE, Dharnidharka VR. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients. Pediatr Transplantation 2010: 14: 145,150. © 2009 Wiley Periodicals, Inc. Abstract:, BKVAN affects about 5% of kidney transplant recipients and may lead to graft failure. Treatment for BKVAN is challenging. Leflunomide, an immunosuppressant with antiviral activity in vitro was used successfully in some adult patients but there are no reports of its use in pediatric patients. We present our experience with three kidney transplant recipients with BKVAN who received leflunomide. Three male patients aged 9, 12, and 20 yr developed BKVAN at 9, 12, and 2 months after a kidney transplant. Immunosuppression was reduced and cidofovir was administered in all patients 2,3 wk apart. Due to inability to travel to receive cidofovir in one, lack of reduction in BK viral load in the second, and rising serum creatinine despite cidofovir in the third patient, we discontinued cidofovir and initiated leflunomide. Teriflunomide target trough levels were 30,60 ,g/mL. The patients received leflunomide for 27, 26, and 24 months, respectively. BK viral load decreased below 1000 DNA copies/mL in one and was undetectable in two patients after beginning leflunomide. All patients tolerated leflunomide without side effects. Leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients. [source] Renal Fanconi syndrome and myopathy after liver transplantation: Drug-related mitochondrial cytopathy?PEDIATRIC TRANSPLANTATION, Issue 1 2008Umut Selda Bayrakci Abstract:, Advances in the field of transplantation provide a better quality of life and allow more favorable conditions for growth and development in children. However, combinations of different therapeutic regimens require consideration of potential adverse reactions. We describe a 15-yr-old girl who had orthotopic liver transplantation because of Wilson's disease. Tacrolimus, MMF, and steroids were given as immunosuppressant. Lamivudine was added because of de nova hepatitis B infection during her follow-up. Three yr after transplantation she developed renal Fanconi syndrome with severe metabolic acidosis, hypophosphatemia, glycosuria, and aminoaciduria. Although tacrolimus was suspected to be the cause of late post-transplant renal acidosis and was replaced by sirolimus, acidosis, and electrolyte imbalance got worse. Proximal muscle weakness has developed during her follow-up. Fanconi syndrome, as well as myopathy, is well recognized in patients with mitochondrial disorders and caused by depletion of mtDNA. We suggest that our patient's tubular dysfunction and myopathy may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine. [source] Efficacy of mizoribine in the treatment of systemic lupus erythematosus in childrenPEDIATRICS INTERNATIONAL, Issue 4 2004Kouichi Yoshidome AbstractBackground:,Mizoribine (MZR) is a novel immunosuppressant developed in Japan. As MZR is reported to be less toxic than other cytotoxic drugs, it is frequently used in Japan in the treatment of adult patients with rheumatoid arthritis or lupus nephritis. The objective of this study was to evaluate the efficacy of MZR in children with SLE. Nine female children with lupus nephritis who had undergone renal biopsy before starting MZR, were involved in this study. Their mean disease duration was 4.8 years at the time MZR treatment was initiated. Patients who had received intensive medications, such as methyl-prednisolone pulse therapy, intravenous cyclophosphamide pulse therapy, and/or other immunosuppressants, within the 4 months prior to the start of the study, were excluded. Methods:,Patients treated with 3 mg/kg per day of MZR were monitored every month for up to 1 year. The efficacy of MZR was evaluated by the changes from baseline values of serum C3, serum C4, anti-dsDNA antibody titer, erythrocyte sedimentation rate (ESR), urinary protein, dosage of prednisolone (PSL), and the sum of the scores defined by these parameters. Results:,Favorable changes were observed in C3 and ESR after 2 months and 3 months of MZR therapy, respectively. At 3 months of MZR therapy, the sum of scores defined by the parameters for disease activity indicated that MZR was more effective in non-class IV nephritis patients (n = 5) than in class IV nephritis patients (n = 4) (P = 0.0197). All nine children involved in the study tolerated the MZR therapy well during the study. Conclusion:,MZR was safe in lupus children, but its efficacy was limited in patients with non-class IV nephritis. Further study is necessary, in which higher dosages and/or earlier use of MZR is provided to a larger number of children. [source] Conventional allogeneic hematopoietic stem cell transplantation for lymphoma may overcome the poor prognosis associated with a positive FDG-PET scan before transplantationAMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2008Akihide Yoshimi A positive scan in pretransplantation fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be associated with a poor prognosis in patients with lymphoma undergoing high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). For those with a positive FDG-PET scan, treatment that includes allogeneic stem cell transplantation (allo-SCT) may be an alternative. However, it is uncertain whether allo-SCT can overcome a poor prognosis. Therefore, we conducted a retrospective analysis of 14 patients with lymphoma who had undergone FDG-PET scan within one month before allo-SCT at our institution. Eleven patients were FDG-PET-positive and three were negative. With a median follow-up of 17 months (range: 6,44) after allo-SCT, the cumulative incidence of progression was 29.3% in FDG-PET-positive patients and 0% in the FDG-PET-negative patients. Four of the 11 patients who had post-transplantation FDG-PET showed FDG-avid lesions on the first post-transplantation scan. In two of the four, regression of the lesions was observed during the scheduled reduction of immunosuppressant without donor lymphocyte infusion and remained without progression at the last follow-up (34 and 8 months). Durable responses after allo-SCT, at least with conventional conditioning regimens, can be expected in patients with FDG-PET-positive lesions before transplantation. Thus, conventional allo-SCT could be an attractive modality compared to ASCT for patients with positive FDG-PET after the completion of conventional salvage chemotherapy, and particularly for patients with T and NK-cell lymphomas. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] FK506 as an adjuvant of tolerogenic DNA vaccination for the prevention of experimental autoimmune encephalomyelitisTHE JOURNAL OF GENE MEDICINE, Issue 11 2009Youmin Kang Abstract Background DNA vaccination is a strategy that has been developed primarily to elicit protective immunity against infection and cancer. Methods DNA vaccine was used, in conjunction with an immunosuppressant, to tolerize harmful autoimmunity. Results Immunization of C57BL/6 mice with MOG35,55, a myelin oligodendrocyte glycoprotein-derived peptide, and FK506 (Tacrolimus) as a tolerogenic adjuvant stimulated regulatory dendritic cells, induced antigen-specific regulatory T cells (Treg), and protected the animals from subsequent induction of experimental autoimmune encephalomyelitis (EAE). After EAE induction, there were fewer lymphocytes, including fewer T helper 17 cells, and more Treg infiltrating the spinal cord in the immunized mice compared to in control mice. Furthermore, at the peak of the EAE manifestation, CD4 T cells in the immunized mice showed decreased expression of interferon-, and interleukin (IL)-17, but not IL-4, in treated mice. Conclusions DNA vaccination, when applied with an immunosuppressant as adjuvant, can induce antigen-specific tolerance and prevent autoimmune disease. Copyright © 2009 John Wiley & Sons, Ltd. [source] REVIEW ARTICLE: Interleukin-10: A Multi-Faceted Agent of PregnancyAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2010Jessica E. Thaxton Citation Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol 2010 It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene,environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal,fetal interface. [source] Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells,THE PROSTATE, Issue 3 2006Qiang Zhang Abstract BACKGROUND TGF-, is a potent immunosuppressant. High levels of TGF-, produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-,-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-,-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-, type II receptor (T,RIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and naïve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-,-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and naïve CD8+ T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-,-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perforin, nitric oxide, IFN-,, IL-2, TNF-, were secreted in tumor tissue treated with tumor-reactive TGF-,-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with naïve T cells and GFP controls. CONCLUSIONS Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-,-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-,-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||||||||